Embolization

ABSTRACT

A particle includes a ferromagnetic material, a radiopaque material, and/or an MRI-visible material.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. §120 to, U.S. patent application Ser. No. 13/605,320, filed Sep.6, 2012, which is a continuation of U.S. patent application Ser. No.13/190,823, filed Jul. 26, 2011, now U.S. Pat. No. 8,273,324, which is acontinuation of U.S. patent application Ser. No. 10/651,475, filed Aug.29, 2003, now U.S. Pat. No. 8,012,454, which is a continuation-in-partof U.S. patent application Ser. No. 10/232,265, filed on Aug. 30, 2002,now U.S. Pat. No. 7,462,366. The entire disclosure of each of theforegoing applications is hereby incorporated by reference for allpurposes.

TECHNICAL FIELD

This invention relates to embolization.

BACKGROUND

Therapeutic vascular occlusions (embolizations) are used to prevent ortreat pathological conditions in situ. Compositions including embolicparticles are used for occluding vessels in a variety of medicalapplications. Delivery of embolic particles through a catheter isdependent on size uniformity, density and compressibility of the embolicparticles.

SUMMARY

In one aspect, the invention features a particle that includes apolymeric matrix and a ferromagnetic material distributed in thepolymeric matrix. The particle has a diameter of from about ten micronsto about 3,000 microns.

In another aspect, the invention features a method of manufacturingparticles. The method includes forming a mixture containing a polymer, agelling compound, and a ferromagnetic material, and treating the mixtureto form a particle that includes the polymeric matrix and theferromagnetic material in the polymeric matrix. The particles have amean diameter of from about ten microns to about 3,000 microns.

In a further aspect, the invention features a method that includesadministering to a subject a therapeutically effective amount of embolicparticles. The particles include a polymeric matrix and a ferromagneticmaterial distributed in the polymeric matrix. The particles have a meandiameter of from about ten microns to about 3,000 microns.

In one aspect, the invention features a particle that includes apolymeric matrix and a radiopaque material distributed in the polymericmatrix. The particle has a diameter of from about ten microns to about3,000 microns. The particle has an interior with a density of lark poresand a surface region with a density of lark pores, and the density oflarge pores of the interior is greater than the density of lark pores ofthe surface region.

In another aspect, the invention features a method of manufacturingparticles. The method includes forming a mixture containing a polymer,chin compound, and a radiopaque material, and treating the mixture toform a particle comprising a polymeric matrix and radiopaque material inthe polymeric matrix. The particles have a diameter of from about tenmicrons to about 3,000 microns. The particles have an interior with adensity of lark pores and a surface region with a density of lark pores,and the density of lark pores of the interior is greater than thedensity of lark pores of the surface region.

In a further aspect, the invention features a method that includesadministering to a subject a therapeutically effective amount of embolicparticles. The particles include a polymeric matrix and a radiopaquematerial distributed in the polymeric matrix. The particles have a meandiameter of from about ten microns to about 3,000 microns. The particleshave an interior with a density of lark pores and a surface region witha density of large pores, and the density of lark pores of the interioris greater than the density of large pores of the surface region.

In one aspect, the invention features a particle that includes apolymeric matrix and an MRI-visible material distributed in thepolymeric matrix, The particle has a diameter of from about ten micronsto about 3,000 microns. The particle has an interior with a density oflark pores and a surface region with a density of lark pores, and thedensity of large pores of the interior is greater than the density oflark pores of the surface region.

In another aspect, the invention features a method of manufacturingparticles. The method includes forming a mixture containing a polymer,gelling compound, and an MRI-visible material, and treating the mixtureto form a particle comprising a polymeric matrix and the MRI-visiblematerial in the polymeric matrix. The particles have a mean diameter offrom about ten microns to about 3,000 microns. The particles have aninterior with a density of lark pores and a surface region with adensity of lark pores, and the density of lark pores of the interior isgreater than the density of lark pores of the surface region.

In a further aspect, the invention features a method that includesadministering to a subject a therapeutically effective amount of embolicparticles. The particles include a polymeric matrix and an MRI-visiblematerial distributed in the polymeric matrix. The particles have a meandiameter of from about ten microns to about 3,000 microns. The particleshave an interior with a density of lark pores and a surface region witha density of lark pores, and the density of lark pores of the interioris greater than the density of lark pores of the surface region.

In another aspect, the invention features a method that includes heatinga plurality of particles disposed in a body lumen. The particles includea polymeric matrix and a ferromagnetic material distributed in thepolymeric matrix. The particles have a diameter of from about tenmicrons to about 3,000 microns.

Embodiments can include one or more of the following.

A ferromagnetic material can be, for example, a metal (e.g., atransition metal), a metal alloy, a metal oxide, a soft ferrite, arare-earth magnet alloy, or an amorphous and non-earth alloy. Examplesof ferromagnetic materials include magnetite, nickel, cobalt, iron andMu-metal.

A radiopaque material can be, for example, a metal, a metal alloy, ametal oxide, or a contrast agent. Examples of radiopaque materialsinclude titanium dioxide, bismuth subcarbonate, platinum and bariumsulfate.

An MRI-visible material can be, for example, a non-ferrous metal-alloycontaining paramagnetic elements, a non-ferrous metallic band coatedwith an oxide or a carbide layer of dysprosium or gadolinium, anon-ferrous metal coated with a layer of superparamagnetic material, ora nanocrystalline particle of a transition metal oxide. Examples ofMRI-visible materials include terbium-dysprosium, dysprosium,gadolinium, Dy₂O₃, and gadolinium-containing compounds (e.g., Gd₂O₃).

The material (ferromagnetic material, radiopaque material, MRI-visiblematerial) can be in the shape of a particle.

The material (ferromagnetic material, radiopaque material, MRI-visiblematerial) can have a diameter of from about two microns to about 20microns (e.g., from about ten microns to about 12 microns).

The material (ferromagnetic material, radiopaque material, MRI-visiblematerial) can be substantially homogeneously distributed in thepolymeric matrix.

A particle containing a polymer matrix and a material (ferromagneticmaterial, radiopaque material, MRI-visible material) can have a diameterof at least about 100 microns (e.g., at least about 500 microns, atleast about 1,000 microns, at least about 1,500 microns, at least about2,000 microns, at most about 2,500 microns) and/or at most about 2,000microns (e.g., at most about 1,500 microns, at most about 1,200 microns,at most about 1,000 microns, at most about 500 microns). For example,such a particle can have a diameter of from about 100 microns to about500 microns, or from about 500 microns to about 1,200 microns.

A particle containing a polymer matrix and a material (ferromagneticmaterial, radiopaque material, MRI-visible material) can also include atherapeutic agent (e.g., in the particle and/or on the particle).

A particle containing a polymer matrix and a material (ferromagneticmaterial, radiopaque material, MRI-visible material) can besubstantially spherical.

The polymeric matrix can include a polysaccharide (e.g., alginate).

The polymeric matrix can be formed of one or more polyvinyl alcohols,polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates,carboxymethyl celluloses, hydroxyethyl celluloses, substitutedcelluloses, polyacrylamides, polyethylene glycols, polyamides,polyureas, polyurethanes, polyesters, polyethers, polystyrenes,polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids, and/orpoly(lactic-co-glycolic) acids.

A particle containing a polymer matrix and a material (ferromagneticmaterial, radiopaque material, MRI-visible material) can include two ormore polymers. For example, one of the polymers can form a coating overanother (e.g., matrix) polymer. The polymer coating can contain one ormore ferromagnetic materials, one or more MRI-visible materials and/orone or more radiopaque materials. The density of the material(s) in thecoating can be less than, greater than, or about the same as the densityof the material(s) in the matrix polymer. The polymer coating can bebioabsorbable (e.g., formed of a polysaccharide such as alginate).

In some embodiments, a particle containing a polymeric matrix and aferromagnetic material can contain pores. In certain embodiments, aparticle containing a polymeric matrix and a ferromagnetic material canbe nonporous.

In some embodiments in which a particle that contains a polymeric matrixand a ferromagnetic material contains pores, the density of large poresin an interior region of the particle can be greater than the density oflarge pores of the surface region.

A particle containing a polymer matrix and a material (ferromagneticmaterial, radiopaque material, MRI-visible material) can contain fromabout 0.1 percent to about 90 percent by weight (e.g., from about 0.1percent to about 75 percent by weight) of the ferromagnetic material,MRI-visible material or radiopaque material.

A particle containing a polymer matrix and a material (ferromagneticmaterial, radiopaque material, MR1-visible material) can have a coatingthat includes an inorganic, ionic salt.

The gelling compound used in a method to make a particle can be apolysaccharide (e.g., alginate).

A method of making a particle can include forming drops of the mixturethat contains the polymer and gelling agent. The method can includecontacting the drops with a gelling agent. The method can furtherinclude reacting the polymer. The method can also include removing thegelling compound. The method can include combining the particles with apharmaceutically acceptable medium.

A method of administering embolic particles can include administrationby percutaneous injection.

A method of administering embolic particles can include administrationby a catheter.

A method of administering embolic particles can include applying amagnetic field to direct the particles. The magnetic field can beexternal to a subject, internal to the subject, or both. The particlescan be directed with a catheter comprising a magnet.

A method of administering embolic particles can include releasing thetherapeutic agent from the particles.

A method can include ablating body tissue.

In some embodiments, heating the particles can include exposing theparticles to RF radiation.

In some embodiments, heating the particles heats body tissue.

Embodiments of the invention may have one or more of the followingadvantages.

In some embodiments, a particle can contain one or more components thatare biocompatible. As an example, a particle can include one or morebiocompatible polymers (e.g., one or more bioabsorable polymers). Asanother example, a particle can contain one or more materials (e.g., oneor more radiopaque materials, one or more ferromagnetic materials, oneor more MRI-visible materials) that are biocompatible. In certainembodiments, a particle can include one or more biocompatible polymers(e.g., one or more bioabsorable polymers) and one or more additionalbiocompatible materials (e.g., one or more radiopaque materials, one ormore ferromagnetic materials, one or more MRI-visible materials).

In embodiments in which a particle contains one or more radiopaquematerials, the particle can exhibit enhanced visibility under X-rayfluoroscopy (e.g., when the particle is in a subject). In certainembodiments, the presence of one or more radiopaque materials can allowthe particle to be viewed using X-ray fluoroscopy in the absence of aradiopaque contrast agent. This can allow a physician or technician toview the particle in an embolic composition (e.g., prior to deliveringthe particles from a catheter) via a non-invasive technique, allow thephysician or technician to position the particles at a desired locationwithin the subject (e.g., by positioning the delivery portion of thecatheter at a desired location within the subject and then deliveringthe embolic composition into the subject), and/or allow the physician ortechnician to monitor the progress of a procedure and/or determinewhether the particles are migrating to a site that is not targeted fortreatment.

In embodiments in which a particle contains one or more MRI-visiblematerials, the particle can exhibit entranced visibility under MRI(e.g., when the particle is in a subject). In certain embodiments, thepresence of one or more MRI-visible materials can allow the particle tobe viewed using MRI in the absence of an MRI contrast agent. This canallow a physician or technician to view the particle in an emboliccomposition (e.g., prior to delivering the particles from a catheter)via a non-invasive technique, allow the physician or technician toposition the particles at a desired location within the subject (e.g.,by positioning the delivery portion of the catheter at a desiredlocation within the subject and then delivering the embolic compositioninto the subject), and/or allow the physician or technician to monitorthe progress of a procedure and/or determine whether the particles aremigrating to a site that is not targeted for treatment.

In embodiments in which a particle contains one or more ferromagneticmaterials, the positioning of the particle can be relatively easilyand/or non-invasively controlled using a magnetic field (e.g., amagnetic field outside a subject, a magnetic field inside a subject, orboth). As an example, the particle can be steered through a body lumen(e.g., to a relatively distal location of a lumen that might otherwisebe difficult for the particle to reach) by applying a magnetic field tothe particle. As another example, the ability of the particle to migratefrom a desired location can be reduced by applying a magnetic field.

In some embodiments (e.g., when a particle contains a ferromagneticmaterial), the particle can enhance RF ablation procedures.

Features and advantages are in the description, drawings, and claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a cross-sectional view of an embodiment of a particle.

FIG. 2A is a schematic of an embodiment of a system for manufacturingparticles, and FIG. 2B is an enlarged schematic of region 2B in FIG. 2A.

FIG. 3A is a schematic illustrating an embodiment of injection of anembolic composition including embolic particles into a vessel, and FIG.3B is an enlarged view of the region 3B in FIG. 3A.

DETAILED DESCRIPTION

Referring to FIG. 1, a substantially spherical particle 10 includes amatrix 12, a material 14 and pores 16. Material 14, which is formed ofone or more radiopaque materials, one or more MR_I-visible materials,and/or one or more ferromagnetic materials, is substantiallyhomogeneously distributed in matrix 12. Pores 16 are regions of particle10 that are substantially devoid of matrix 12 and material 14. In someembodiments, pores 16 contain a gas, such as air.

In general, particle 10 has a diameter of about 3,000 microns or less(e.g., about 2,500 microns or less; about 2,000 microns or less; about1,500 microns or less; about 1,200 microns or less; about 1,000 micronsor less; about 900 microns or less; about 700 microns or less; about 500microns or less; about 400 microns or less; about 300 microns or less;about 100 microns or less) and/or about ten microns or more (e.g., about100 microns or more; about 300 microns or more; about 400 microns ormore; about 500 microns or more; about 700 microns or more; about 900microns or more; about 1,000 microns or more; about 1,200 microns ormore; about 1,500 microns or more; about 2,000 microns or more; about2,500 microns or more). In certain embodiments, the diameter of particle10 can be from about 100 microns to about 700 microns; from about 500microns to about 700 microns; from about 100 microns to about 500microns; from about 100 microns to about 300 microns; from about 300microns to about 500 microns; from about 500 microns to about 1,200microns; from about 500 microns to about 700 microns; from about 700microns to about 900 microns; from about 900 microns to about 1,200microns.

As shown in FIG. 1, particle 10 can be considered to include a centerregion, C, from the center e′ of particle 10 to a radius of about r/3, abody region, B, from about r/3 to about 2r/3, and a surface region, S,from about 2r/3 to r. The regions can be characterized by the relativesize of pores 16 present in particle 10 in each region, the density ofpores 16 (the number of pores 16 per unit volume of particle 10) in eachregion, and/or the mass density (the density of the matrix 12 andmaterial 14 mass per unit volume of particle 10) in each region.

In general, the mean size of pores 16 in region C of particle 10 isgreater than the mean size of pores 16 at region S of particle 10. Insome embodiments, the mean size of pores 16 in region C of particle 10is greater than the mean size of pores 16 in region B particle 10,and/or the mean size of pores 16 in region B of particle 10 is greaterthan the mean size of pores 16 at region S particle 10. In someembodiments, the mean size of pores 16 in region C is about 20 micronsor more (e.g., about 30 microns or more, from about 20 microns to about35 microns). In certain embodiments, the mean size of pores 16 in regionB is about 18 microns or less (e.g., about 15 microns or less, fromabout 18 microns to about two microns). In some embodiments, the meansize of pores 16 in region S is about one micron or less (e.g., fromabout 0.1 micron to about 0.01 micron). In certain embodiments, the meansize of pores 16 in region B is from about 50 percent to about 70percent of the mean size of pores 16 in region C, and/or the mean sizeof pores 16 at region S is about ten percent or less (e.g., about twopercent or less) of the mean size of pores 16 in region B. In someembodiments, the surface of particle 10 and/or its region S is/aresubstantially free of pores having a diameter greater than about onemicron (e.g., greater than about ten microns). In certain embodiments,the mean size of pores 16 in the region from 0.8 r to r (e.g., from 0.9r to r) is about one micron or less (e.g., about 0.5 micron or less,about 0.1 micron or less). In some embodiments, pores 16 in the regionfrom the center of particle 10 to 0.9 r (e.g., from the center ofparticle 10 to 0.8 r) are about ten microns or greater and/or have amean size of from about two microns to about 35 microns. In certainembodiments, the mean size of pores 16 in the region from 0.8 r to r(e.g., from 0.9 r to r) is about five percent or less (e.g., about onepercent or less, about 0.3 percent or less) of the mean size of pores 16in the region from the center to 0.9 r. In some embodiments, the largestpores in particle 10 can have a size in the range of about one percentor more (e.g., about five percent or more., about ten percent or more)of the diameter of particle 10. The size of pores 16 in particle 10 canbe measured by viewing a cross-section of particle 10. For irregularlyshaped (nonspherical) pores, the maximum visible cross-section is used.

Generally, the density of pores 16 in region C of particle 10 is greaterthan the density of pores 16 at region S of particle 10. In someembodiments, the density of pores 16 in region C of particle 10 isgreater than the density of pores 16 in region B of particle 10, and/orthe density of pores 16 in region B of particle 10 is greater than thedensity of pores 16 at region S of particle 10.

In general, the mass density in region C of particle 10 is less than themass density at region S of particle 10. In some embodiments, the massdensity in region C of particle 10 is less than the mass density inregion B of particle 10, and/or the mass density in region B of particle10 is less than the mass density at region S of particle 10.

In general, the density of particle 10 (e.g., as measured in grams ofmaterial per unit volume) is such that it can be readily suspended in acarrier fluid (e.g., a pharmaceutically acceptable carrier, such as asaline solution, a contrast solution, or a mixture thereof) and remainsuspended during delivery. In some embodiments, the density of particle10 is from about 1.1 grams per cubic centimeter to about 1.4 grams percubic centimeter. As an example, for suspension in a saline-contrastsolution, the density of particle 10 can be from about 1.2 grams percubic centimeter to about 1.3 grams per cubic centimeter.

In certain embodiments the region of small pores near the surface ofparticle 10 can be relatively stiff and incompressible, which canenhance resistance to shear forces and abrasion. In addition, thevariable pore size profile can produce a symmetric compressibility and,it is believed, a compressibility profile. As a result, particle 10 canbe relatively easily compressed from a maximum, at rest diameter to asmaller, compressed first diameter. Compression to an even smallerdiameter, however, may involve substantially greater force. Withoutwishing to be bound by theory, it is believed that a, variablecompressibility profile can be the result of a relatively weak,collapsible inter-pore wall structure in the center region of particle10 (where the pores are relatively large), and a stiffer inter-pore wallstructure near the surface of particle 10 (where the pores are morenumerous and relatively small). It is further believed that a variablepore size profile can enhance elastic recovery after compression. It isalso believed that the pore structure can influence the density ofparticle 10 and the rate of carrier fluid or body fluid uptake.

In some embodiments, a plurality of the particles (e.g., in an emboliccomposition) can be delivered through a catheter having a lumen with across-sectional area that is smaller (e.g., about 50 percent or less)than the uncompressed cross-sectional area of the particles. In suchembodiments, the particles are compressed to pass through the catheterfor delivery into the body. Typically, the compression force is providedindirectly, by depressing the syringe plunger to increase the pressureapplied to the carrier fluid. In general, the particles are relativelyeasily compressed to diameters sufficient for delivery through thecatheter into the body. The relatively robust, rigid surface region ofthe particles can resist abrasion when the particles contact hardsurfaces such as syringe surfaces, hard plastic or metal stopcocksurfaces, and/or the catheter lumen wall (made of, e.g., Teflon) duringdelivery. Once in the body, the particles can substantially recover tooriginal diameter and shape for efficient transport in the carrier andbody fluid stream. At the point of occlusion, the particles can againcompress as they aggregate in the occlusion region. The particles canform a relatively dense occluding mass. The compression of the particlesin the body is generally determined by the force provided by body fluidflow in the lumen. In some embodiments, the compression may be limitedby the compression profile of the particles, and the number of particlesneeded to occlude a given diameter may be reduced.

In certain embodiments, the sphericity of particle 10 after compressionin a catheter (e.g., after compression to about 50 percent or more ofthe cross-sectional area of particle 10) is about 0.8 or more (e.g.,about 0.85 or more, about 0.9 or more, about 0.95 or more, about 0.97 ormore). Particle 10 can be, for example, manually compressed, essentiallyflattened, while wet to about 50 percent or less of its originaldiameter and then, upon exposure to fluid, regain a sphericity of about0.8 or more (e.g., about 0.85 or more, about 0.9 or more, about 0.95 ormore, about 0.97 or more). As referred to herein, the sphericity of aparticle is calculated using the equations in Appendix A. The relevantparameters of a particle can be determined using a Beckman CoulterRapidVUE Image Analyzer version 2.06 (Beckman Coulter, Miami, Fla.).

Porous particles are described, for example, in U.S. patent applicationSer. No. ______ [Attorney Docket No. 01194-465001], filed on Aug. 8,2003, and entitled “Embolization”, which is incorporated herein byreference.

In general, matrix 12 is formed of one or more polymers. Examples ofpolymers include polyvinyl alcohols, polyacrylic acids, polymethacrylicacids, poly vinyl sulfonates, carboxymethyl celluloses, hydroxyethylcelluloses, substituted celluloses, polyacrylamides, polyethyleneglycols, polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids),and copolymers or mixtures thereof. In some embodiments, matrix 12 canbe substantially formed of a highly water insoluble, high molecularweight polymer. An example of such a polymer is a high molecular weightpolyvinyl alcohol (PVA) that has been acetalized. Matrix 12 can besubstantially pure intrachain 1,3-acetalized PVA and substantially freeof animal derived residue such as collagen. In some embodiments,particle 10 includes a minor amount (e.g., about 2.5 weight percent orless, about one weight percent or less, about 0.2 weight percent orless) of a gelling material (e.g., a polysaccharide, such as alginate).In certain embodiments, the majority (e.g., at least about 75 weightpercent, at least about 90 weight percent, at least about 95 weightpercent) of matrix 12 is formed of a bioabsorbable polymer (e.g.,polysaccharide, such as alginate).

In general, the amount of matrix 12 contained in particle 10 can bevaried as desired. In some embodiments, particle 10 can include about99.9 percent by weight or less (e.g., about 99.5 percent by weight orless, about 99 percent by weight or less, about 95 percent by weight orless, about 90 percent by weight or less, about 80 percent by weight orless, about 70 percent by weight or less, about 60 percent by weight orless, about 50 percent by weight or less, about 40 percent by weight orless, about 30 percent by weight or less, about 20 percent by weight orless) and/or about ten percent by weight or more (e.g., about 20 percentby weight or more, about 30 percent by weight or more, about 40 percentby weight or more, about 50 percent by weight or more, about 60 percentby weight or more, about 70 percent by weight or more, about 80 percentby weight or more, about 90 percent by weight or more, about 95 percentby weight or more) of matrix 12.

In sonic embodiments, material 14 is formed of one or more ferromagneticmaterials. As used herein, a ferromagnetic material refers to a materialthat has a magnetic susceptibility of at least about 0.075 or more(e.g., at least about 0.1 or more; at least about 0.2 or more; at leastabout 0.3 or more; at least about 0.4 or more; at least about 0.5 ormore; at least about one or more; at least about ten or more; at leastabout 100 or more; at least about 1,000 or more; at least about 10,000or more) when measured at 25° C. A ferromagnetic material can be, forexample, a metal (e.g., a transition metal such as nickel, cobalt, oriron), a metal alloy (e.g., a nickel-iron alloy such as Mu-metal), ametal oxide (e.g., an iron oxide such as magnetite), a ceramicnanomaterial, a soft ferrite (e.g., nickel-zinc-iron), a magnet alloy(e.g., a rare earth magnet alloy such as a neodymium-iron-boron alloy ora samarium-cobalt alloy), an amorphous alloy (e.g., iron-silicon-boron),a non-earth alloy, or a silicon alloy (e.g., aniron-zirconium-copper-boron-silicon alloy, aniron-zirconium-copper-boron-silicon alloy). Magnetite is commerciallyavailable from FerroTec Corporation (Nashua, N.H.), under the tradenameEMG 1111 Ferrofluid. Iron-copper-niobium-boron-silicon alloys arecommercially available from Hitachi Metals of America under thetradename Finemet™. Iron-zirconium-copper-boron-silicon alloys arecommercially available from MAGNETEC GmbH under the tradename Nanoperm®.

In embodiments in which material 14 is a ferromagnetic material, amagnetic source can be used to move or direct the particles to atreatment site (see discussion below). The magnetic source can beexternal to the subject's body, or can be used internally. In somecases, both an external magnetic source and an internal magnetic sourcecan be used to move the particles. An example of an internal magneticsource is a magnetic catheter, Magnetic catheters are described in U.S.patent application Ser. No. 10/108,874, filled on Mar. 29, 2002, andentitled “Magnetically Enhanced Injection Catheter”, which isincorporated herein by reference. An example of an external magneticsource is a magnetic wand.

In some embodiments in which material 14 is a ferromagnetic material,the particles can be used to enhance the effects of an ablationprocedure (e.g., an RF ablation procedure). For example, the particlescan be used to enhance the ablation of a tumor. First, an RF probe(e.g., a 3.5 centimeter coaxial LeVeen electrode, available fromRadioTherapeutics, Mountain View, Calif.) having tines at one end can beinserted into the area of the tumor. The particles can then be deliveredto the area around the tines of the RF probe by, e.g., a catheter or asyringe. Thereafter, the tines can be deployed and the RF probe can beactivated so that RF energy flows through the tines, thereby heating thetissue around the tines. Eventually, the tumor tissue can die as aresult of the heating. Because they include ferromagnetic material,which can be relatively conductive, the particles can enhance theeffects of ablation. For example, the circuit can be maintained for alonger period of time, resulting, e.g., in an increase in the area ofthe ablated surface. The end of the ablation period can be defined, forexample, by the temperature of the ablated tissue or by the measuredimpedance of the circuit.

In certain embodiments in which material 14 is a ferromagnetic material,a magnetic field can be applied to the particles to affect the extent ofconductivity. The magnetic field can be varied to adjust theconductivity of the particles (and, therefore, to adjust the extent ofheating and ablation).

In some embodiments in which material 14 is a ferromagnetic material,the particles can be used in an agitation ablation process. In such aprocess, a magnetic field can be used to agitate the particles, suchthat the particles heat and/or physically deform the surrounding tissue,thereby ablating the surrounding tissue.

In some embodiments, material 14 is formed of one or more radiopaquematerials. As used herein, a radiopaque material refers to a materialhaving a density of about ten grams per cubic centimeter or greater(e.g., about 25 grams per cubic centimeter or greater, about 50 gramsper cubic centimeter or greater). A radiopaque material can be, forexample, a metal (e.g., tungsten, tantalum, platinum, palladium, lead,gold, titanium, silver), a metal alloy (e.g., stainless steel, an alloyof tungsten, an alloy of tantalum, an alloy of platinum, an alloy ofpalladium, an alloy of lead, an alloy of gold, an alloy of titanium, analloy of silver), a metal oxide (e.g., titanium dioxide, zirconiumoxide, aluminum oxide), bismuth subcarbonate, or barium sulfate. In someembodiments, a radiopaque material is a radiopaque contrast agent.Examples of radiopaque contrast agents include OmnipaqueTm, Renocal,iodiamide meglumine, diatrizoate meglumine, ipodate calcium, ipodatesodium, iodamide sodium, iothalamate sodium, iopamidol, and metrizamide.Radiopaque contrast agents are commercially available from, for example,Bracco Diagnostic.

In embodiments in which material 14 is formed of one or more radiopaquematerials, particle 10 can exhibit enhanced visibility under X-rayfluoroscopy, such as when particle 10 is in a subject (see discussionbelow). In some embodiments, X-ray fluoroscopy can be performed withoutthe use of a radiopaque contrast agent.

In some embodiments, material 14 can include one or more MRI-visiblematerials. As used herein, a MRI-visible material refers to a materialthat has a magnetic susceptibility of at most about one or less (e.g.,at most about 0.5 or less; at most about zero or less) when measured at25° C. An MRI-visible material can be, for example, a non-ferrousmetal-alloy containing paramagnetic elements (e.g., dysprosium orgadolinium) such as terbium-dysprosium, dysprosium, and gadolinium; anon-ferrous metallic band coated with an oxide or a carbide layer ofdysprosium or gadolinium (e.g., Dy₂O₃ or Gd₂O₃); a non-ferrous metal(e.g., copper, silver, platinum, or gold) coated with a layer ofsuperparamagnetic material, such as nanocrystalline Fe₃O₄, CoFe₂O₄,MnFe₂O₄, or MgFe₂O₄; or nanocrystalline particles of the transitionmetal oxides (e.g., oxides of Fe, Co, Ni). In some embodiments in whichmaterial 14 is formed of a ferromagnetic material, material 14 can alsoserve as an MRI-visible material if material 14 is present in asufficiently low concentration. In some embodiments, an MRI-visiblematerial can be an MRI contrast agent. Examples of MRI contrast agentsinclude superparamagnetic iron oxides (e.g., ferumoxides, fenicarbotran,ferumoxsil, ferumoxtran (e.g., ferumoxtran-10), PEG-feron,ferucarbotran); gadopentetate dimeglumine; gadoterate meglumine;gadodiamide; gadoteridol; gadoversetamide; gadobutrol; gadobenatedimeglumine; mangafodipir trisodium; gadoxetic acid; gadobenatedimeglumine; macromolecular Gd-DOTA derivate; gadobenate dimeglumine;gadopentetate dimeglumine; ferric ammonium citrate; manganese chloride;manganese-loaded zeolite; ferristene; perfluoro-octylbromide; and bariumsulfate. MRI contrast agents are described, for example, in U.S. patentapplication Ser. No. 10/390,202, filed on Mar. 17, 2003, and entitled“Medical Devices”, which is incorporated herein by reference.

In embodiments in which material 14 is formed of one or more MRI-visiblematerials, particle 10 can exhibit enhanced visibility using MRI, suchas when particle 10 is in a subject (see discussion below). In someembodiments, MRI can be performed without the use of an MRI contrastagent.

In certain embodiments, material 14 can be biocompatible. As an example,material 14 can be a biocompatible ferromagnetic material (e.g.,magnetite). As another example, material 14 can be a biocompatibleradiopaque material (e.g., magnetite). As an additional example,material 14 can be a biocompatible MRI-visible material (e.g.,magnetite, gadolinium).

In some embodiments, material 14 can be bioerodable, such that material14 can eventually break down in the body and either be dispersedthroughout the body or excreted from the body. For example, material 14can be a bioerodable ferromagnetic material. In such cases, material 14may interfere with MRI-visibility when used in the body in a highconcentration and/or a condensed form (e.g., when used in a particle).However, as material 14 is bioeroded and dispersed throughout the bodyor excreted from the body, its interference with MRI-visibility candecrease. Thus, a bioerodable ferromagnetic material 14 can be used, forexample, for short-term embolic applications, without permanentlyinterfering with MRI-visibility.

In some embodiments, both material 14 and matrix 12 can bebiocompatible. For example, matrix 12 can be a polysaccharide (e.g.,alginate), while material 14 is a biocompatible material (e.g.,magnetite).

Generally, the amount of material 14 contained within particle 10 can bevaried as desired. In some embodiments, particle 10 can include morethan about 0.1 percent by weight (e.g., more than about 0.5 percent byweight, more than about one percent by weight, more than about fivepercent by weight, more than about ten percent by weight, more thanabout 20 percent by weight, more than about 30 percent by weight, morethan about 40 percent by weight, more than about 50 percent by weight,more than about 60 percent by weight, more than about 70 percent byweight, more than about 80 percent by weight) and/or less than about 90percent by weight (e.g., less than about 80 percent by weight, less thanabout 70 percent by weight, less than about 60 percent by weight, lessthan about 50 percent by weight, less than about 40 percent by weight,less than about 30 percent by weight, less than about 20 percent byweight, less than about ten percent by weight, less than about fivepercent by weight, less than about one percent by weight, less thanabout 0.5 percent by weight) of material 14.

In certain embodiments in which material 14 includes one or moreferromagnetic materials, particle 10 can include from about 0.1 percentby weight to about 90 percent by weight (e.g., from about 0.1 percent byweight to about 75 percent by weight, from about 0.1 percent by weightto about 50 percent by weight, from about one percent by weight to about25 percent by weight) of the ferromagnetic material(s).

In some embodiments in which material 14 includes one or more radiopaquematerials, particle 10 can include from about 0.1 percent by weight toabout 50 percent by weight (e.g., from about 0.1 percent by weight toabout 20 percent by weight, from about one percent by weight to about 20percent by weight) of the radiopaque material(s).

In certain embodiments in which material 14 includes one or moreMRI-visible materials, particle 10 can include from about five percentby weight to about 50 percent by weight (e.g., from about ten percent byweight to about 30 percent by weight) of the MRI-visible material(s).

In general, material 14 can be in any desired form (e.g., a solid, aliquid) and any desired shape (e.g., one or more particles, one or morefibers, one or more flakes, and/or one or more powders). In someembodiments, material 14 (e.g., a particle of material 14, a fiber ofmaterial 14, a flake of material 14, a powder of material 14) can have awidth or diameter, and/or length, of less than about 40 microns (e.g.,less than about 35 microns, less than about 30 microns, less than about25 microns, less than about 20 microns, less than about 15 microns, lessthan about ten microns, less than about five microns, less than aboutone micron, less than about 0.5 micron, less than about 0.1 micron, lessthan about 0.05 micron, less than about 0.03 micron, less than about0.01 micron) and/or more than about 0.005 micron (e.g., more than about0.01 micron, more than about 0.03 micron, more than about 0.05 micron,more than about 0.1 micron, more than about 0.5 micron, more than aboutone micron, more than about five microns, more than about ten microns,more than about 15 microns, more than about 20 microns, more than about25 microns, more than about 30 microns, more than about 35 microns). Insome embodiments, material 14 (e.g., a particle of material 14, a fiberof material 14, a flake of material 14, a powder of material 14) canhave a width or diameter, and/or a length, of from about two microns toabout 20 microns (e.g., from about ten microns to about 12 microns).

As used herein, a fiber of material 14 has a ratio of its largest lineardimension to its smallest linear dimension of at least about 2:1 (e.g.,at least about 3:1, at least about 5:1, at least about 10:1, at leastabout 15:1). In some embodiments, a fiber of material 14 has a ratio ofits largest linear dimension to its smallest linear dimension of at mostabout 20:1 (e.g., at most about 15:1, at most about 10:1, about mostabout 5:1, at most about 3:1). In some embodiments, material 14 includesa mixture of fibers having two or more different aspect ratios.

In general, various methods can be used to prepare particle 10. In someembodiments, particle 10 is formed using a drop generator.

FIG. 2A shows an embodiment of a system for producing particle 10. Thesystem includes a flow controller 300, a drop generator 310, a gellingvessel 320, a reactor vessel 330, a gel dissolution chamber 340 and afilter 350. As shown in FIG. 2B, flow controller 300 delivers asolution, that contains the material of matrix 12 (e.g., one or morepolymers) and a gelling precursor (e.g., alginate) to a viscositycontroller 305, which heats the solution to reduce viscosity prior todelivery to drop generator 310. The solution passes through an orificein a nozzle in drop generator 310, forming drops of the solution. Thedrops are then directed into gelling vessel 320, where the drops contacta gelling agent (e.g., calcium chloride) and are stabilized by gelformation. The gel-stabilized drops are transferred from gelling vessel320 to reactor vessel 330, where the polymer in the gel-stabilized dropsis reacted (e.g., cross-linked), forming precursor particles. Theprecursor particles are transferred to gel dissolution chamber 340,where the gelling precursor is removed. The particles are then filteredin filter 350 to remove debris, and are sterilized and packaged as anembolic composition including the particles. Methods of making particlesare described, for example, in U.S. patent application Ser. No. ______[Attorney Docket No. 01194-465001], filed on Aug. 8, 2003, and entitled“Embolization”, which is incorporated herein by reference.

In some embodiments in which a drop generator is used in the preparationof particle 10, material 14 is included in the solution delivered by thedrop generator, and the solution is processed as described above to formparticle 10. In certain embodiments in which a drop generator is used inthe preparation of particle 10, material 14 is included in the gellingvessel so that material 14 is incorporated into the drop when the dropcontacts the gelling agent. Combinations of these methods can be used.

In some embodiments, material 14 is added to particle 10 in a separateoperation. For example, material 14 can be applied to the surface ofparticle 10 by compounding matrix material 12 with one or more of thecoating materials (described below) and then applying the compoundedcoating material to the surface of particle 10. In certain embodiments,material 14 can be placed in particle 10 (e.g., in one or more pores 16or cavities of particle 10). In embodiments in which material 14 is inliquid form (e.g., a contrast agent) prior to being incorporated intoparticle 10, material 14 can be incorporated into the particles by, forexample, absorption. Combinations of these methods can be used. Forexample, in some embodiments, one material can be incorporated into acavity in a particle, while another material (either the same as, ordifferent from, the first material) can be absorbed through the surfaceof the particle.

In some embodiments, multiple particles are combined with a carrierfluid (e.g., a saline solution, a contrast agent, or both) to form anembolic composition. Such embolic compositions can be used in, forexample, neural, pulmonary, and/or AAA (abdominal aortic aneurysm)applications. The compositions can be used in the treatment of, forexample, fibroids, tumors, internal bleeding, arteriovenousmalformations (AVMs), and/or hypervascular tumors. The compositions canbe used as, for example, fillers for aneurysm sacs, AAA sac (Type IIendoleaks), endoleak sealants, arterial sealants, and/or puncturesealants, and/or can be used to provide occlusion of other lumens suchas fallopian tubes. Fibroids can include uterine fibroids which growwithin the uterine wall (intramural type), on the outside of the uterus(subserosal type), inside the uterine cavity (submucosal type), betweenthe layers of broad ligament supporting the uterus (interligamentoustype), attached to another organ (parasitic type), or on a mushroom-likestalk (pedunculated type). Internal bleeding includes gastrointestinal,urinary, renal and varicose bleeding. AVMs are for example, abnormalcollections of blood vessels, e.g., in the brain, which shunt bloodfront a high pressure artery to a low pressure vein, resulting inhypoxia and malnutrition of those regions from which the blood isdiverted. In some embodiments, a composition containing the particlescan be used to prophylactically treat a condition.

The magnitude of a dose of an embolic composition can vary based on thenature, location and severity of the condition to be treated, as well asthe route of administration. A physician treating the condition, diseaseor disorder can determine an effective amount of embolic composition. Aneffective amount of embolic composition refers to the amount sufficientto result in amelioration of symptoms or a prolongation of survival ofthe subject. The embolic compositions can be administered aspharmaceutically acceptable compositions to a subject in anytherapeutically acceptable dosage, including those administered to asubject intravenously, subcutaneously, percutaneously, intratrachealy,intramuscularly, intramucosaly, intracutaneously, intra-articularly,orally or parenterally.

An embolic composition can be prepared in calibrated concentrations ofthe particles for case of delivery by the physician. Suspensions of theparticles in saline solution can be prepared to remain stable (e.g., tonot precipitate) over a duration of time. A suspension of the particlescan be stable, for example, for from about one minute to about 20minutes (e.g., from about one minute to about ten minutes, front abouttwo minutes to about seven minutes, from about three minutes to aboutsix minutes). The concentration of particles can be determined byadjusting the weight ratio of the particles to the physiologicalsolution. If the weight ratio of the particles is too small, then toomuch liquid could be injected into a blood vessel, possibly allowing theparticles to stray into lateral vessels. In some embodiments, thephysiological solution can contain from about 0.01 weight percent toabout 15 weight percent of the particles. A composition can include amixture of particles, such as particles including ferromagneticmaterial, and particles including radiopaque material.

Referring to FIGS. 3A and 3B, an embolic composition, including embolicparticles 111 and a carrier fluid, is injected into a vessel through aninstrument such as a catheter 150. Catheter 150 is connected to asyringe barrel 110 with a plunger 160. Catheter 150 is inserted, forexample, into a femoral artery 120 of a subject. Catheter 150 deliversthe embolic composition to, for example, occlude a uterine artery 130leading to a fibroid 140. Fibroid 140 is located in the uterus of afemale subject. The embolic composition is initially loaded into syringe110, Plunger 160 of syringe 110 is then compressed to deliver theembolic composition through catheter 150 into a lumen 165 of uterineartery 130.

Referring particularly to FIG. 3B, which is an enlarged view of section3B of FIG. 3A, uterine artery 130 is subdivided into smaller uterinevessels 70 (e.g., having a diameter of about two millimeters or less)which feed fibroid 140. The embolic particles 111 in the emboliccomposition partially or totally fill the lumen of uterine artery 130,either partially or completely occluding the lumen of the uterine artery130 that feeds uterine fibroid 140.

In some embodiments, among the particles delivered to a subject in anembolic composition, the majority (e.g., about 50 percent or more, about60 percent or more, about 70 percent or more, about 80 percent or more,about 90 percent or more) of the particles have a diameter of about3,000 microns or less (e.g., about 2,500 microns or less; about 2,000microns or less; about 1,500 microns or less; about 1,200 microns orless; about 900 microns or less; about 700 microns or less; about 500microns or less; about 400 microns or less; about 300 microns or less;about 100 microns or less) and/or about ten microns or more (e.g., about100 microns or more; about 300 microns or more; about 400 microns ormore; about 500 microns or more; about 700 microns or more; about 900microns or more; about 1,200 microns or more; about 1,500 microns ormore; about 2,000 microns or more; about 2,500 microns or more).

In certain embodiments, the particles delivered to a subject in anembolic composition have a mean diameter of about 3,000 microns or less(e.g., about 2,500 microns or less; about 2,000 microns or less; about1,500 microns or less; about 1,200 microns or less; about 900 microns orless; about 700 microns or less; about 500 microns or less; about 400microns or less; about 300 microns or less; about 100 microns or less)and/or about ten microns or more (e.g., about 100 microns or more; about300 microns or more; about 400 microns or more; about 500 microns ormore; about 700 microns or more; about 900 microns or more., about 1,200microns or more; about 1,500 microns or more; about 2,000 microns ormore; about 2,500 microns or more). Exemplary ranges for the meandiameter of particles delivered to a subject include from about 100microns to about 300 microns; from about 300 microns to about 500microns; from about 500 microns to about 700 microns; and from about 900microns to about 1,200 microns. In general, the particles delivered to asubject in an embolic composition have a mean diameter in approximatelythe middle of the range of the diameters of the individual particles,and a variance of about 20 percent or less (e.g., about 15 percent orless, about ten percent or less).

In some embodiments, the mean size of the particles delivered to asubject in an embolic composition can vary depending upon the particularcondition to be treated. As an example, in embodiments in which theparticles in an embolic composition are used to treat a liver tumor, theparticles delivered to the subject can have a mean diameter of about 500microns or less (e.g., from about 100 microns to about 300 microns; fromabout 300 microns to about 500 microns). As another example, inembodiments in which the particles in an embolic composition are used totreat a uterine fibroid, the particles delivered to the subject in anembolic composition can have a mean diameter of about 1,200 microns orless (e.g., from about 500 microns to about 700 microns; from about 700microns to about 900 microns; from about 900 microns to about 1,200microns).

While certain embodiments have been described, the invention is not solimited.

As an example, in some embodiments, a particle can contain combinationsof different types of materials (e.g., one or more ferromagneticmaterials and one or more radiopaque materials; one or more radiopaquematerials and one or more MRI-visible materials; one or moreferromagnetic materials and one or more MRI-visible materials; one ormore MRI-visible materials, one or more ferromagnetic materials, and oneor more radiopaque materials).

As another example, a particle can be prepared (e.g., for use in anembolic composition) without removal of the gelling precursor (e.g.,alginate). Such particles can be prepared, for example, using a dropgenerator as described above, but without removing the gelling precursorfrom the particle after cross-linking.

As an additional example, in some embodiments a particle can include oneor more therapeutic agents (e.g., drugs). The therapeutic agent(s) canbe in and/or on the particle. Therapeutic agents include agents that arenegatively charged, positively charged, amphoteric, or neutral.Therapeutic agents can be, for example, materials that are biologicallyactive to treat physiological conditions; pharmaceutically activecompounds; gene therapies; nucleic acids with and without carriervectors; oligonucleotides; gene/vector systems; DNA chimeras; compactingagents (e.g., DNA compacting agents); viruses; polymers; hyaluronicacid; proteins (e.g., enzymes such as ribozymes); cells (of humanorigin, from an animal source, or genetically engineered); stem cells;immunologic species; nonsteroidal anti-inflammatory medications; oralcontraceptives; progestins; gonadotrophin-releasing hormone agonists;chemotherapeutic agents; and radioactive species (e.g., radioisotopes,-radioactive molecules). Non-limiting examples of therapeutic agentsinclude anti-thrombogenic agents; antioxidants; angiogenic andanti-angiogenic agents and factors; anti-proliferative agents (e.g.,agents capable of blocking smooth muscle cell proliferation);anti-inflammatory agents; calcium entry blockers;antineoplastic/antiproliferative/anti-mitotic agents (e.g., paclitaxel,doxorubicin, cisplatin); antimicrobials; anesthetic agents;anti-coagulants; vascular cell growth promoters., vascular cell growthinhibitors; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vasoactive mechanisms; and survivalgenes which protect against cell death. Therapeutic agents aredescribed, for example, in co-pending U.S. patent application Ser. No.10/615,276, filed on Jul. 8, 2003, and entitled “Agent DeliveryParticle”, which is incorporated herein by reference.

As a further example, in some embodiments a particle can be coated(e.g., with a bioabsorable material). For example, a particle caninclude a polyvinyl alcohol matrix polymer with a sodium alginatecoating. The coating can contain, for example, one or more therapeuticagents. In certain embodiments, a particle can be coated to include ahigh concentration of one or more therapeutic agents and/or loaded intothe interior of the particle. The surface can release an initial dosageof therapeutic agent after which the body of the particle can provide aburst release of therapeutic agent. The therapeutic agent on the surfacecan be the same as or different from the therapeutic agent in the bodyof the particle. The therapeutic agent on the surface can be applied byexposing the particle to a high concentration solution of thetherapeutic agent. The therapeutic agent coated particle can includeanother coating over the surface the therapeutic agent (e.g., adegradable and/or bioabsorbable polymer which erodes when the particleis administered). The coating can assist in controlling the rate atwhich therapeutic agent is released from the particle. For example, thecoating can be in the form of a porous membrane. The coating can delayan initial burst of therapeutic agent release. The coating can beapplied by dipping or spraying the particle. The erodible polymer can bea polysaccharide (such as an alginate). In some embodiments, the coatingcan be an inorganic, ionic salt. Other erodible coatings include watersoluble polymers (such as polyvinyl alcohol, e.g., that has not beencross-linked), biodegradable poly DL-lactide-poly ethylene glycol(PELA), hydrogels (e.g., polyacrylic acid, haluronic acid, gelatin,carboxymethyl cellulose), polyethylene glycols (PEG), chitosan,polyesters (e.g., polycaprolactones), and poly(lactic-co-glycolic) acids(e.g., poly(d-lactic-co-glycolic) acids). The coating can includetherapeutic agent or can be substantially free of therapeutic agent. Thetherapeutic agent in the coating can be the same as or different from anagent on a surface layer of the particle and/or within the particle. Apolymer coating, e.g., an erodible coating, can be applied to theparticle surface in cases in which a high concentration of therapeuticagent has not been applied to the particle surface. In some embodiments,the coating can include a ferromagnetic material, a radiopaque material,and/or an MRI-visible material. Alternatively or in addition, theparticle interior can include a ferromagnetic material, a radiopaquematerial, and/or an MRI-visible material. The coating can include ahigher, equal, or lower concentration of ferromagnetic material,radiopaque material, and/or MRI-visible material relative to theparticle interior. In some embodiments, the interior of the particle caninclude one type of material (e.g., a ferromagnetic material), while thecoating includes a different type of material (e.g., a radiopaquematerial). Coatings arc described, for example, in U.S. patentapplication Ser. No. 10/615,276, filed on Jul. 8, 2003, and entitled“Agent Delivery Particle”, which is incorporated herein by reference.

As an additional example, in some embodiments one or more particlesis/are substantially nonspherical. In some embodiments, particles can beshaped (e.g., molded, compressed, punched, and/or agglomerated withother particles) at different points in the particle manufacturingprocess. In some embodiments (e.g., where the matrix polymer is apolyvinyl alcohol and the gelling precursor is sodium alginate), aftercontacting the particles with the gelling agent but beforecross-linking, the particles can be physically deformed into a specificshape and/or size. After shaping, the matrix polymer (e.g., polyvinylalcohol) can be cross-linked, optionally followed by substantial removalof the gelling precursor (e.g., alginate). While substantially sphericalparticles are preferred, non-spherical particles can be manufactured andformed by controlling, for example, drop formation conditions. In someembodiments, nonspherical particles can be formed by post-processing theparticles (e.g., by cutting or dicing into other shapes). Particleshaping is described, for example, in co-pending U.S. patent applicationSer. No. 10/402,068, filed Mar. 28, 2003, and entitled “Forming aChemically Cross-Linked Particle of a Desired Shape and Diameter”, whichis incorporated herein by reference.

As a further example, in some embodiments the particles can be used fortissue bulking. As an example, the particles can be placed (e.g.,injected) into tissue adjacent to a body passageway. The particles cannarrow the passageway, thereby providing bulk and allowing the tissue toconstrict the passageway more easily. The particles can be placed in thetissue according to a number of different methods, for example,percutaneously, laparoscopically, and/or through a catheter. In certainembodiments, a cavity can be formed in the tissue, and the particles canbe placed in the cavity. Particle tissue bulking can be used to treat,for example, intrinsic sphincteric deficiency (ISD), vesicoureteralreflux, gastroesophageal reflux disease (CiERD), and/or vocal cordparalysis (e.g., to restore glottic competence in cases of paralyticdysphonia). In some embodiments, particle tissue bulking can be used totreat urinary incontinence and/or fecal incontinence. The particles canbe used as a graft material or a filler to fill and/or to smooth outsoft tissue defects, such as for reconstructive or cosmetic applications(e.g., surgery). Examples of soft tissue defect, applications includecleft lips, scars (e.g., depressed scars from chicken pox or acnescars), indentations resulting from liposuction, wrinkles (e.g.,glabella frown wrinkles), and soft tissue augmentation of thin lips.Tissue bulking is described, for example, in co-pending U.S. patentapplication Ser. No. 10/231,664, filed on Aug. 30, 2002, and entitled“Tissue Treatment”, which is incorporated herein by reference.

As an additional example, in certain embodiments one or moreferromagnetic materials, one or more MRI-visible materials and/or one ormore radiopaque materials can be nonhomogeneously distributed in aparticle. As an example, the density of the ferromagnetic, MRI-visibleand/or radiopaque material(s) can, be higher in the center region of theparticle than at the surface region of the particle. As another example,the density of the ferromagnetic, MRI-visible and/or radiopaquematerial(s) can be higher at the surface region of the particle than inthe center region of the particle.

As another example, in certain embodiments a particle can have a cavity(a portion that is substantially devoid of a matrix material such as amatrix polymer) that has a diameter of at least about 50 microns (e.g.,at least about 100 microns, at least about 150 microns). In someembodiments, such a cavity can contain one or more ferromagneticmaterials, one or more MRI-visible materials and/or one or moreradiopaque materials. In such embodiments, the ferromagnetic,MRI-visible and/or radiopaque material(s) can be nonhomogeneouslydistributed in the particle.

As a further example, in some embodiments one or more ferromagneticmaterials, one or more MRI-visible materials and/or one or moreradiopaque materials can be located at the surface of the particle. Insuch embodiments, the interior of the particle can be substantiallydevoid the ferromagnetic, MRI-visible and/or radiopaque material(s), orthe interior of the particle can further include the ferromagnetic,MRI-visible and/or radiopaque material(s).

As an additional example, in certain embodiments one or moreferromagnetic materials, one or more MRI-visible materials and/or one ormore radiopaque materials can be attached to the surface of a particle(e.g., via a chemical linker).

As another example, in some embodiments a particle can be formed with nopores and/or no cavities.

As a further example, in some embodiments a particle can be formedwithout pores (nonporous panicle).

Other embodiments are in the claims

1-18. (canceled)
 19. A particle, comprising a polymeric matrix and aradiopaque material distributed in the polymeric matrix, wherein theparticle has a diameter of from about ten microns to about 3,000microns, and wherein the particle has an interior with a density oflarge pores and a surface region with a density of large pores, and thedensity of large pores of the interior is greater than the density oflarge pores of the surface region.
 20. The particle of claim 19, whereinthe radiopaque material is selected from the group consisting of metals,metal alloys, and contrast agents.
 21. The particle of claim 19, whereinthe radiopaque material comprises a member selected from the groupconsisting of titanium dioxide and bismuth subcarbonate.
 22. Theparticle of claim 19, wherein the radiopaque material comprises platinumor barium sulfate.
 23. The particle of claim 19, wherein the radiopaquematerial is substantially homogeneously distributed throughout thepolymeric matrix.
 24. The particle of claim 19, wherein the polymericmatrix comprises a polysaccharide.
 25. The particle of claim 19, whereinthe polymeric matrix comprises a member selected from the aroupconsisting of polyvinyl alcohols, polyacrylic acids, polymethaerylleacids, poly vinyl sulfonates, carboxyrnethyl celluloses, hydroxyethylcelluloses, substituted celluloses, polyacrylamides, polyethyleneglycols, polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co-glycolic) acids, and combinations thereof.
 26. Theparticle of claim 19, wherein the particle further comprises therapeuticagent.
 27. The particle of claim 19, wherein the polymeric matrixcomprises a first polymer and a second polymer.
 28. The particle ofclaim 27, wherein the second polymer forms a coating over the firstpolymer.
 29. The particle of claim 19, wherein the particle issubstantially spherical.
 30. The particle of claim 19, wherein theparticle comprises from about 0.1 percent to about 50 percent by weightof the radiopaque material. 31-64. (canceled)
 65. A method of treating apatient, comprising: disposing at least one particle in a tissue of asubject, the at least one particle having a diameter of at most about3,000 microns; and exposing the at least one particle to radiation andthereby heating. the tissue to at least one of a predetermined thresholdtemperature and a predetermined threshold impedance.
 66. The method ofclaim 65, wherein heating the tissue comprises ablating the tissue. 67.The method of claim 65, wherein the radiation is RF radiation.
 68. Themethod of claim 65, wherein the particle includes a conductive material.69. The method of claim 65, wherein the particle includes a gel.